Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.O[CH2:36][CH2:37][CH2:38][N:39]1[C:44](=[O:45])[CH2:43][O:42][CH2:41][C:40]1=[O:46].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:36][CH2:37][CH2:38][N:39]4[C:44](=[O:45])[CH2:43][O:42][CH2:41][C:40]4=[O:46])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: O=C1COCC(=O)N1CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCN1C(=O)COCC1=O
Product: Cl
Reaction time: 6 h
Yield: 18.3 %

Procedure:
Diethyl azodicarboxylate (567 μl, 3.6 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (383 mg, 1.2 mmol), (prepared as described for the starting material in Example 2), 4-(3-hydroxypropyl)-3,5-dioxomorpholine (291 mg, 1.68 mmol) and triphenylphosphine (944 mg, 3.6 mmol) in methylene chloride (10 ml) under nitrogen. The mixture was sired at ambient temperature for 6 hours and the insolubles were removed by filtration. The filtrate was purified by pouring it directly on to a column of silica and eluting with methylene chloride/acetonitrile/methanol (60/34/6 followed by 60/24/16 and 60/16/24). The semi-purified product was repurified by column chromatography eluting with methylene chloride/acetonitrile/methanol (5/4/1). The purified product was dissolved in methylene chloride/methanol 2M ethereal hydrogen chloride (1 ml) was added and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-(3-(3,5-dioxomorpholino)propoxy)-6-methoxyquinazoline hydrochloride (56 mg, 10%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]([N:23]3[CH2:26][CH:25]([C:27]([O:29]C)=[O:28])[CH2:24]3)=[O:22])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([C:21]([N:23]3[CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]3)=[O:22])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)NO)n2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(C(=O)O)C2)no1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A solution of methyl 1-[(5-{(1R)-4-cyclohexyl-1 -[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazol-3-yl)carbonyl]-3-azetidinecarboxylate (Example 18) (130 mg, 0.31 mmol) in 1,4-dioxane (33 ml) was cooled to 0° C. and treated with lithium hydroxide monohydrate (25 mg, 0.60 mmol). The mixture was stirred for 1 hour being allowed to warm to room temperature over this time. Further lithium hydroxide monohydrate (25 mg, 0.60 mmol) was added and the mixture stirred for 3 hours. The mixture was then treated with hydrochloric acid (2M), diluted with water and extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by HPLCb to afford the title compound as a foam (110 mg).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:26](O)=[O:27])[CH2:3][C:4]1[N:8]=[CH:7][N:6](C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[CH:5]=1.[NH2:46][C@@H:47]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C@@H:48]([OH:54])[C@H:49]([CH:51]1[CH2:53][CH2:52]1)[OH:50].N1CCCCC1>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)[C:26]([NH:46][C@@H:47]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C@@H:48]([OH:54])[C@H:49]([CH:51]1[CH2:52][CH2:53]1)[OH:50])=[O:27]
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)[C@@H](O)C1CC1
Reactant: O=C(N[C@@H](Cc1cn(C(=O)OCC2c3ccccc3-c3ccccc32)cn1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In an analogous manner to that described in Example 1, paragraph (c), by the condensation of Fmoc-His(Fmoc)-OH and (1S,2R,3S)-3-amino-1-cyclopropyl-4-phenyl-1,2-butanediol followed by cleavage of the protecting groups using piperidine in methylene chloride there was obtained (S)-α-amino-N-[(1S,2R,3S)-1-benzyl-3-cyclopropyl-2,3-dihydroxypropyl]-imidazole-4-propionamide as a colourless foam, MS: 359 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=O)(C)(C)C.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([O:43][CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[C:32]([CH:34]=[N:35][C:36]([O:38][Si](C)(C)C)=[CH2:37])[CH:33]=1>C1(C)C=CC=CC=1.ClCCl>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([O:43][CH:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[C:32]([CH:34]2[C:10]3([C:11]4[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=4)[NH:8][C:9]3=[O:26])[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:37][C:36](=[O:38])[NH:35]2)[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cc(Br)ccc1OC1CCOCC1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2OC2CCOCC2)N1
Yield: 49.3 %

Procedure:
In a manner similar to the method described in example 32d, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 5b (1.0 g, 2.5 mmol) was reacted with 1-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (4 g, 10 mmol) in toluene at 140° C., then treated with trifuloroacetic acid in dicloromethane to give racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(tetrahydro-pyran-4-yloxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 0.76 g, 49%)
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](O)[CH2:12][CH2:13][CH3:14].C1C=CC=CC=1.S(=O)(=O)(O)O>O>[SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5]
Reactant: O=C(O)c1ccccc1S
Reactant: CCCCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCCCOC(=O)c1ccccc1S
Yield: 68.6 %

Procedure:
Using a procedure similar to that of Example IV, a mixture of 50 g (0.32 mole) of 2-mercaptobenzoic acid, 50 g (0.7 mole) of n-butanol, 200 ml of benzene and 1.1 g of sulfuric acid (93%) was heated at reflux for 24 hours during which time 5.9 ml of water was collected in the water separator. The mixture was cooled, washed, concentrated and the residual oil distilled to give n-butyl 2-mercaptobenzoate: 46.1 g (68.6% yield); bp 127°-128°C/ 1.0 mm; mol wt 210:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH2:33]([N:40]=[C:41]=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>N1C=CC=CC=1>[C:3]([OH:31])(=[O:42])[CH3:4].[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:41]([NH:40][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:42])=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C=NCc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.082 g, 0.000188 mol) was dissolved in anhydrous pyridine (1 mL), benzyl isocyanate (0.025 g, 0.000188 mol) was added and the resulting solution was stirred at ambient temperature for 20 hours. The solvent was removed under reduced pressure and the resulting residue purified by preparative HPLC (Hypersil C 18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-N′-benzylurea acetate (0.009 g, 0.0000142 mol) as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=C[CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN1CC(N)C1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][CH:44]5[CH2:43][N:48]([CH3:47])[CH2:45]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine hydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.82 (m, 12H) 2.32 (s, 3H) 3.10 (s, 3H) 3.62 (s, 2H) 3.95 (s, 3H) 4.06 (t, J=13.4 Hz, 2H) 4.47 (m, 1H) 4.45 (d, J=6.8 Hz, 1H) 7.49 (d, J=8.1 Hz, 1H) 7.53 (s, 1H) 7.90 (s., 1H) 8.21 (s, 1H) 8.28 (d, J=8.1 Hz, 1H) 8.65 (d, J=5.8 Hz, 1H). [M+H] calc'd for C26H33F2N7O3, 530. found 530.
Reaction SMILES: [C:1]([C@H:4]1[N:7]([CH:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6](=[O:27])[C@@H:5]1[C@H:28]([OH:30])[CH3:29])([OH:3])=[O:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:38]O>>[CH3:38][O:2][C:1]([C@H:4]1[N:7]([CH:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:6](=[O:27])[C@@H:5]1[C@H:28]([OH:30])[CH3:29])=[O:3]
Reactant: CO
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Temperature: 40 °C

Procedure:
To a solution of (3S,4S)-4-carboxy-3-(1-(R)-hydroxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (34 g) in methanol (310 ml) was added 98% sulfuric acid (2.9 g), and the resultant mixture was heated at 65° C. for 3 hours, cooled down to 40° C., neutralized with 8% sodium hydroxide (15 ml) and concentrated to make a one third volume. The concentrate was diluted with 1,2-dichloroethane (105 ml) and washed with water. The aqueous layer was separated from the organic layer and extracted with 1,2-dichloroethane (105 ml). The extracts and the organic layer were combined together, washed with water and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave (3S,4S)-4-methoxycarbonyl-3-(1-(R)-hydroxyethyl)-1-di(p-anisyl)methyl-2-azetidinone. m.p., 102°-104° C.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].CN(C=O)C.[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[N+:17]=[N-:18])[CH3:13].CCOCC>C(Cl)(Cl)Cl>[CH2:12]([O:14][C:15](=[O:19])[C:16](=[N+:17]=[N-:18])[CH:2]=[O:3])[CH3:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(C=O)=[N+]=[N-]
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 13.6 %

Procedure:
Oxalyl chloride (4.7 g, 3.1 mL, 37.0 mmol) was added to a cold (0-4° C.) solution of DMF (2.25 g, 2.4 mL, 30.8 mmol) in CHCl3 (20 mL) and stirring was continued for 10 minutes. The reaction mixture was heated at 40° C. for 10 minutes and cooled to −10° C. Diazo-acetic acid ethyl ester (3.5 g, 3.5 mL, 30.6 mmol) was then added and stirred at room temperature for 1 hr. Reaction mixture was concentrated to get the residue. Ether was then added, filtered the solid precipitated and dissolved in 10% aq HAc (10 mL) and stirring was continued for 1 hr. The reaction mixture was extracted with ether, washed with saturated sodium bicarbonate solution and brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 590 mg (21% Yield) of 2-diazo-3-oxo-propionic acid ethyl ester. 1H NMR (CDCl3): δ 9.7 (s, 1H), 4.4 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]2[CH2:7][S:8][CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:4]2[NH:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[CH:50]1[C:62]2[CH:61]([CH2:63][O:64][C:65](=[O:82])[NH:66][C:67]3[CH:72]=[CH:71][C:70]([NH2:73])=[C:69]([O:74][CH2:75][C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=4)[CH:68]=3)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1>CC(N(C)C)=O>[CH:50]1[C:62]2[CH:61]([CH2:63][O:64][C:65](=[O:82])[NH:66][C:67]3[CH:72]=[CH:71][C:70]([NH:73][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]4[CH:4]5[CH:5]([NH:6][C:2](=[O:1])[NH:3]5)[CH2:7][S:8]4)=[C:69]([O:74][CH2:75][C:76]4[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=4)[CH:68]=3)[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]=2[CH:53]=[CH:52][CH:51]=1
Reactant: O=C(O)CCCCC1SCC2NC(=O)NC21
Reactant: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCC1SCC2NC(=O)NC21)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoic acid (388) (0.293 g, 1.2 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HBTU) (0.455 g, 1.2 mmol) were combined and dissolved in DMA (24 mL). iPr2EtN (0.313 mL, 1.8 mmol) was added and the mixture was shaken for 30 minutes at room temperature. The (4-amino-3-benzyloxy-phenyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (65) (0.25 g, 0.573 mmol) was added and the mixture was shaken in a 40 mL I-Chem vial for 16 h. LC-MS indicated complete coupling at this point. The mixture was poured into ice-water and a very pale/purple powder precipitated. Collection by filtration under reduced pressure followed by drying under high vacuum for 16 h gave the desired product (389) as a white/purple solid (0.28 g, 0.422 mmol, 73.7% yield). LC-MS (ESI): (exact mass: 662.26) m/e 663.2 [M+1]+ (100%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23].[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([F:35])=[CH:27][C:26]=1F.C([O-])([O-])=O.[Na+].[Na+].O>CS(C)=O>[F:24][C:25]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([F:35])=[CH:27][C:26]=1[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23]
Reactant: N[C@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Reactant: CS(=O)(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cc(F)c(N[C@H]2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1F
Temperature: 130 °C
Reaction time: 18 h
Yield: 64.6 %

Procedure:
A solution of (S)-benzyl 4-(3-amino-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.5, 7.9 mmol) (Preparation E, Step D), 1,2,4-trifluoro-5-(methylsulfonyl)benzene (3.3 g, 16 mmol), and Na2CO3 (2.5 g, 24 mmol) in DMSO (20 mL) was degassed using nitrogen and was stirred at 130° C. for 18 hours in a sealed tube. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered then concentrated in vacuo. The material was purified over silica gel (100% EtOAc) to yield (S)-benzyl 4-(3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.6 g, 5.1 mmol, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14](OC)=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[S:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:21].[CH3:30][OH:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:18]([O:31][CH3:30])=[C:12]([CH:13]=[C:14]=[O:15])[NH:11][C:10]([CH3:19])=[C:9]1[S:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:21]
Reactant: CO
Reactant: COC(=O)C1=C(C)NC(C)=C(S(=O)c2ccc(OC)cc2)C1c1ccccc1Cl
Product: COC1=C(C=C=O)NC(C)=C(S(=O)c2ccc(OC)cc2)C1c1ccccc1Cl

Procedure:
A solution of (-)-4-methoxyphenylsulfinylacetone (10.0 g), prepared as in Preparation II above, 2-chlorobenzaldehyde (7.3 g), and NH4OAc (100 mg) in toluene (150 ml) was heated at reflux using a Dean-Stark water separator for 2 hours. About 90 ml of the solvent was removed in vacuo. Methyl β-aminocrotonate (11.5 g) and methanol (75 ml) were added to the remaining solution. After heating at reflux for 20 hours, the reaction mixture was cooled and evaporated to dryness. The residue was chromatographed on silica gel (1:1 dichloromethane/ethyl acetate) to give the two pure sulfinyldihydropyridine diastereomers in a ratio of approximately 10:1. The major isomer was (-)-4-(2-chlorophenyl)-3-(4-methoxyphenyl)sulfinyl-5-methoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine, m.p. 188°-190° C., [α]D =-27° (C=0.060, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:20]([CH3:21])[CH2:19][CH2:18][C@:14]45[C:15]=2[C:16]=1[O:17][CH:13]4[C:12](=[O:22])[CH2:11][CH2:10][C@@:9]35[O:23][CH3:24].[Cl-:25].[NH4+]>[Zn].C(O)C>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:20]([CH3:21])[CH2:19][CH2:18][C@@:14]4([C:15]=2[C:16]=1[OH:17])[C@@:9]3([O:23][CH3:24])[CH2:10][CH2:11][C:12](=[O:22])[CH2:13]4
Reactant: COc1ccc2c3c1OC1C(=O)CC[C@@]4(OC)[C@@H](C2)N(C)CC[C@]314
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@]1(OC)CCC(=O)C3
Product: Cl
Yield: 145.3 %

Procedure:
A mixture of 15 (1.67 g), Zn dust (0.72 g), ammonium chloride (1.1 g) and ethanol (45 ml) was refluxed for 6 hour under N2 atmosphere. The product was filtered and the residual solid washed with ethanol. The filtrate was concentrated under reduced pressure to give the hydrochloride salt of 16 as a white solid (2.71 g). This product contained some ammonium chloride but was used without purification in the next reaction. Attempts to purify the material by preparation of the free base resulted in loss of material.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1/[CH:15]=[CH:16]/[C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:18]>CO.[Pd]=O>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[CH3:9][C:10]1[NH:14][CH:13]=[N:12][C:11]=1[CH2:15][CH2:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:18]
Reactant: Cc1[nH]cnc1/C=C/C(=O)c1ccc2ccccc2c1
Agent: O=[Pd]
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: Cc1[nH]cnc1CCC(=O)c1ccc2ccccc2c1
Yield: 69.6 %

Procedure:
A solution of (E)-3-(5-methyl-1H-imidazol-4-yl)-1-(2-naphthalenyl)-2-propen-1one maleate (300 mg) in hot methanol (90 ml) was hydrogenated at room temperature and atmospheric pressure over a stirred suspension of pre-reduced 10% palladium oxide on carbon (50% aqueous paste; 30 mg) in methanol (10 ml) for 16 h. The suspension was filtered, evaporated in vacuo, and the residual oil (ca. 350 mg) was partitioned between dichloromethane (3×50 ml) and 2N sodium carbonate (50 ml). The combined organic extracts were dried and evaporated in vacuo. The residual oil (300 mg) was dissolved in absolute ethanol (6 ml) and treated with a solution of maleic acid (100 mg) in ethanol (1 ml). Dilution with dry ether (ca. 75 ml) afforded the title compound (210 mg) as a solid, m.p. 137°-138°, t.l.c. (System A, 89:10:1) Rf 0.33.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: NC(CO)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NC(CO)CO)c(Nc2ccc(I)cc2F)cc1=O
Yield: 34 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (5:1) and treated with 2-amino-1,3-propandiol as for example 34. After workup, the residue was further purified by flash chromatography on silica gel (5% MeOH/CH2Cl2—10% MeOH/CH2Cl2 gradient elution) to give 4-(2-fluoro-4-iodoanilino)-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (34%) as a white solid; m.p. (EtOAc/Hexane) 93-98° C. (glue-liquid). 1H NMR [400 MHz, CH3OD] δ 8.22 (s, 1H), 7.61 (dd, J=9.9, 1.8 Hz, 1H), 7.58-7.54 (m, 1H), 7.21 (t, J=8.4, 1H), 5.78 (d, J=1.1 Hz, 1H), 4.12 (p, J=5.6 Hz, 1H), 3.72 (ddd, J=15.1, 11.2, 5.6 Hz, 4H), 3.51 (s, 3H). HRMS (FAB+) calcd for C16H18FIN3O4 462.0326 (M+), found 462.0323. HPLC 89.9% (254 nm).
Reaction SMILES: C([C:3]1[S:7][C:6]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[C:12]([O:23][CH:24]([CH3:26])[CH3:25])[CH:11]=2)=[N:5][CH:4]=1)=O.[C:28]([CH:33]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:30][CH2:31][CH3:32])=[O:29].[CH2:53]1COCC1>>[CH2:31]([O:30][C:28](=[O:29])[CH:33]=[CH:53][C:3]1[S:7][C:6]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[C:12]([O:23][CH:24]([CH3:25])[CH3:26])[CH:11]=2)=[N:5][CH:4]=1)[CH3:32]
Reactant: C1CCOC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)Nc2ncc(C=O)s2)c1
Product: CCOC(=O)C=Cc1cnc(NC(=O)c2cc(Oc3ccccc3)cc(OC(C)C)c2)s1
Yield: 67 %

Procedure:
3-[2-(3-Isopropoxy-5-phenoxybenzoylamino)-thiazol-5-yl]-acrylic acid ethyl ester (102 mg, 67%) was prepared from N-(5-formylthiazol-2-yl)-3-isopropoxy-5-phenoxybenzamide (130 mg, 0.34 mmol) and (carboethoxymethylene)triphenylphospho-rane (150 mg, 0.43 mmol) by heating a THF solution (5.0 mL) of the reactants at 50° C. overnight. Molecular sieves (4A) were added to remove any water in the reaction.